DESCRIPTION: (Applicant's Abstract) Studies of the etiology of addiction have been limited in part by difficulty in obtaining homogeneous addiction populations, reinforcing the need to develop new pathophysiological models of addiction. Pathological gambling (PG) is a chronic, disabling, and understudied impulse control disorder which affects 1-3% of the population. PG is often viewed as an addiction, consisting of tolerance, dependence, and withdrawal. Up to half of pathological gamblers have substance use problems. Prior studies have suggested serotonergic and noradrenergic abnormalities in PG. Our pharmacological treatment studies with the serotonin reuptake blocker fluvoxamine revealed a reduction in actual pathological gambling behavior. In pilot pharmacological challenge studies, the partial 5-HT agonist m-CPP induced a "high" behavioral response and an augmented prolactin response in PG patients compared to normal controls. The alpha-2 agonist clonidine induced an augmented growth hormone response in PG. This pattern of response, not seen before in other impulsive, compulsive, and depressive conditions, may reflect behavioral initiation/ disinhibition and behavioral readiness, respectively, key features of PG relevant to addiction. To examine serotonergic and noradrenergic responsiveness in PG, this proposal will compare 70 PG patients (35 males, 35 females) and 40 normal controls (20 males, 20 females) of comparable marginal distribution of age, sex, SES, and ethnicity on behavioral (high) and neuroendocrine (prolactin, GH) response to m-CPP and clonidine, controlling for pulsatile neuroendocrine factors. Specificity of noradrenergic and serotonergic systems with regard to behavioral readiness vs. behavioral initiation/disinhibition, respectively, will be examined. Severity of impulsivity and depression will be correlated with these serotonergic and noradrenergic measures. Understanding the etiology of PG will facilitate the development of pathophysiological models of addiction.